This project will examine the actions of volatile anesthetics on transmitter-gated membrane channels. Three goals will be pursued. First, quantitative dose-effect data will be acquired to allow determination of the likelihood that the effects are present at clinically relevant concentrations. In comparison to similar data obtained on other channels, this will allow assessment on the relative importance of the actions in producing clinical effects. Second, effects on receptors which are particular to anesthetics will be identified. To do this, the actions of two volatile anesthetics and a volatile convulsant will be examined. Finally, the underlying mechanism of action of the drugs on receptors will be explored. To reach these goals, two types of receptors will be studied. It has been proposed that anesthesia may reflect the ability of volatile anesthetics to enhance the activation of the major receptor type involved in inhibitory neurotransmission in the brain (the gamma-aminobutyric acid receptor, GABAAR). This project proposes to examine the effects of volatile agents on GABAAR-mediated transmission between cultured cerebellar neurons. To study the mechanism of enhancement, analysis of actions on synaptic transmission will be extended with studies of GABA-evoked whole- cell and single channel currents. The nicotinic acetylcholine receptor (AChR) of skeletal muscle is the protypical member of the transmitter-gated channel family (the GABAAR is a member of this extended gene family). It has been reported that VA block AChR function, and hence reduce excitatory synaptic transmission mediated by AChR activation. Therefore, this project will also examine the blocking effects of VA on both adult- and fetal-type AChR. The observations made with AChR will be compared and contrasted to the results from studies of GABAAR, to determine whether there are common features in the effects. The results should lead to insights into the likely mechanisms by which anesthetics affect the function of receptors for neurotransmitters. Furthermore, they should indicate whether actions on receptors are likely to underlie the clinically desired effects of these drugs. Finally, in the context of the other projects in this program, they will indicate the range of effects which anesthetics have on several identified channels involved in synaptic transmission, and result in a better understanding of the cellular effects associated with anesthesia.